Developing new ways to treat prostate cancer is a significant challenge. Prostate cancer is the second leading cause of cancer-related deaths for men in the United States. In 2011, this resulted in an estimated 34,000 deaths. Prostate cancer therapeutic options are limited to surgery and/or combinations of chemotherapy and radiation. Unfortunately, late-stage diagnosis of prostate cancer renders current therapies ineffective. The effectiveness of relatively new targeted treatments remains to be shown. There is an urgent major unmet medical need for the development of selective treatments for prostate cancer. Our new approach to prostate cancer is completely different and focuses on inhibition of a key molecular pathway by a non-toxic compound. We have discovered and optimized a small molecule (i.e., 3) that selectively and potently inhibits a key molecular pathway. The overall Goal is to test this novel small molecule as an inhibitor to suppress prostate cancer progression by targeting a key signaling pathway and enhance currently used chemotherapeutics. Compound 3 is non-toxic, pharmaceutically suitable for in vivo applications, and possesses a novel mechanism of action. Based on extensive in vitro and in vivo preliminary data, we have strong support that 3 will inhibit prostate cancer proliferation in vivo and enhance currently used chemotherapeutics. The novelty of this project comes from the unique druggable target of the proposed anti-prostate cancer compound. The hypothesis that inhibition of a single molecular pathway can result in blocking three mechanisms of prostate cancer including proliferation, migration and apoptosis and also enhance currently used chemotherapeutics is novel. The proposed work can be readily accomplished because of the expertise of the team. The work will be divided into two straightforward Specific Aims. The Aims of the work include: 1a) Show that lead compound 3 has chemical and metabolic stability, 1b) Do IND-enabling safety and PK studies of 3 in preparation for orthotopic xenograft studies and 2) Do efficacy studies of 3 in the presence and absence of enzalutamide in subcutaneous and human patient-derived intrafemoral bone niche xenograft models to show enhanced inhibition of tumor growth and pathology of xenografts in mice. The results obtained will afford fundamental information about a new approach to treat prostate cancer. The development of non-toxic inhibitors of molecular pathways crucial to prostate cancer represents a novel approach and addresses a major unmet medical need because the clinical utility of available approaches for treating bone niche human prostate cancer is limited. We hypothesize that lead compound 3 will enhance enzalutamide inhibition of prostate cancer proliferation in an in vivo orthotopic xenograft animal model of prostate cancer with minimal side effects and thus provide feasibility of a novel therapeutic strategy to treat prostate cancer.